An important objective of combinatorial chemistry is to generate a large number of novel compounds that can be screened to identify lead compounds for pharmaceutical research and drug development. Theoretically, the total number of compounds which may be produced for a given library is limited only by the number of reagents available to form substituents on the variable positions on the library's molecular scaffold. The combinatorial process lends itself to automation, both in the generation of compounds and in their biological screening, thereby enhancing greatly the opportunity and efficiency of drug discovery.
Combinatorial chemistry may be performed in a manner where libraries of compounds are generated as mixtures, while the complete identification of the individual compounds is postponed until after positive screening results are obtained. However, a preferred form of combinatorial chemistry is “parallel array synthesis”, (also called Multiple Parallel Synthesis, MPS) where individual reaction products are simultaneously synthesized, but are retained in separate compartments [Geysen et al. (1984); Houghten (1985)]. For example, the individual library compounds can be prepared, stored, and assayed in separate wells of a microtiter plate, each well containing one member of the parallel array. The use of standardized microtiter plates or equivalent apparatus is advantageous because such an apparatus is readily accessed by programmed robotic machinery, both during library synthesis and during library sampling or assaying.
Combinatorial chemistry can be carried out in solution phase where both reactants are dissolved in solution or in solid phase where one of the reactants is covalently bound to a solid support. Solid phase synthesis offers the advantage that reactions can be carried out using excess reagents, while the solid support-bound products are easily washed free of excess reagent. The use of excess reagents may ensure high yield of each step in a multiple step synthesis. Solution phase synthesis typically requires use of one or more reaction mixture work-up procedures to separate to reaction product from unreacted excess reagent.
The first combinatorial libraries were composed of peptides, in which all or selected amino acid positions were randomized [Geysen et al. (1984); Furka et al. (1991)]. Peptides and proteins can exhibit high and specific binding activity, and can act as catalysts. In consequence, they are of great importance in biological systems. Unfortunately, peptides per se have limited utility for use as therapeutic entities. They are costly to synthesize, unstable in the presence of proteases, non selective and in general do not pass cellular membranes.
Nucleic acids have also been used in combinatorial libraries. Their great advantage is the ease with which a nucleic acid with appropriate binding activity can be amplified. As a result, combinatorial libraries composed of nucleic acids can be of low redundancy and hence, of high diversity. However, the resulting oligonucleotides are not suitable as drugs for several reasons. First, the oligonucleotides have high molecular weights and cannot be synthesized conveniently in large quantities. Second, because oligonucleotides are polyanions, they do not cross cell membranes. Finally, deoxy- and ribo-nucleotides are hydrolytically digested by nucleases that occur in all living systems and are therefore usually decomposed before reaching the target.
There has therefore been much interest in combinatorial libraries based on small molecules (i.e. molecules having molecular weight of up to about 1000 daltons), which are more suited to pharmaceutical use, especially those which, like benzodiazepines, belong to a chemical class which has already yielded useful pharmacological agents [Bunin and Ellman (1992); Beeley (2000)]. The techniques of combinatorial chemistry have been recognized as the most efficient means for finding small molecules that act on these targets. At present, small molecule combinatorial chemistry involves the synthesis of either pooled or discrete molecules that present varying arrays of functionality on a common scaffold. These compounds are grouped in libraries that are then screened against the target of interest either for binding or for inhibition of biological activity [Adang and Hermkens (2001)].
The elements of diversity in libraries of currently available scaffold based compounds having the general structure (A) shown below, are based mainly on sequential or positional diversity namely the order in which the various R groups are arranged around the ring and chemical diversity that can arise from alterations in the chemical nature of the R groups.

In the above structure (A), X, Y and Z represent ring heteroatoms or carbons, and R′, R″ and R′″ represent substituents associated to the ring through a linker (showed schematically as a wavy line).
It is known from the art [Kumar S. et al. (2000)] that molecules may bind to each other if their conformations are complementary in geometry and chemistry and if their binding produces stable associations. However, most of the known libraries of organic molecules suffer from a major drawback when applied for the discovery of new drug leads based on the inhibition of peptide:protein or protein:protein or protein:nucleic acid interactions: they are too constrained and therefore lack the ability to undergo conformational complementarity, i.e. lack an ability for binding to a protein and/or a nucleic acid. This led to the preparations of extremely large libraries (consist of up to millions of compounds) and their biological screening, which in many cases results in the discovery of low affinity leads or to the lack of their discovery.
There is thus an urgent need in the art to develop new combinatorial libraries comprising molecules having a flexible scaffold backbone that are conformationally flexible and thus have the ability to undergo conformational complementarity. Such libraries will be useful in the screening for drug candidates for a variety of uses in medicine.